Globally, approximately 34 million people are infected with human immunodeficiency virus (HIV), and sub- Saharan Africa is the region with the highest prevalence of infections. The incidence rate remains stubbornly high at 2.5 million new infections each year. In parallel with the global HIV/AIDS pandemic, unplanned pregnancies account for nearly half of all pregnancies worldwide and lead to almost 100,000 maternal deaths per year as a result of unsafe abortions and complications of pregnancy and delivery. The only anti-HIV microbicide with proof of concept data is tenofovir vaginal gel, dosed in an intermittent, pericoital regimen. Adherence in HIV prevention studies involving daily dosing regimens has generally been poor. The inability to demonstrate statistically significant efficacy for TFV 1% gel in the VOICE trial (once daily dosing with vaginal TFV 1% gel) was due to low adherence. Less than 30% of trial participants used the product per protocol. Similarly, low product adherence was most likely responsible for the inability to demonstrate effectiveness of oral tenofovir disoproxil fumarate (TDF)/emtricitabine in the Fem-PrEP trial. We propose to address these problems by developing an innovative intrauterine system (IUS) releasing a highly potent prodrug of tenofovir (TFV), tenofovir alafenamide fumarate (TAF) for a minimum of 1 year. TAF is a new, stable, lymphoid-targeting prodrug of TFV, which is undergoing late-stage clinical testing as an oral HIV treatment. TAF is 1000 times more potent than TFV and more stable and potent than the prodrug TDF (Viread(R)). TAF will be released continuously in combination with copper (Cu) from the IUS. Cu IUSs are one of the most well-established and cost-effective long-acting reversible contraceptives used and accepted around the world, which also provide non-hormonal benefits. Once an IUS is inserted, women have effective, discreet protection with 100% adherence, until the system is removed by a trained provider in a simple and fast office procedure. The main goal of this project is to demonstrate that TAF can be delivered from an IUS at a rate that provides effective levels of TFV-diphosphate (TFV-DP), the active metabolite, to local genital tissues (endometrium, cervix and vagina) and prevents HIV infection in the female reproductive tract. Benchmarks for pharmacokinetics (PK) (e.g., TFV-DP concentrations in vaginal lymphocytes) will be based on existing in vivo data. Safety and PK of early device prototypes will be assessed in the rabbit model. Safety, PK and efficacy of a lead IUS will be assessed in the low-dose repeat challenge nonhuman primate model in collaboration with the Centers for Disease Control team who developed this model. Success of the proposed work will provide women with access to an inexpensive, discreet, long-acting IUS that is safe and effective to prevent unintended/mistimed pregnancy and HIV infection, and will lead to a paradigm shift in the fields of HIV pre-exposure prophylaxis, contraception, and women's overall reproductive health.